Abstract 1541: NextGen conditionally active biologic (CAB) anti-Nectin-4-ADC with improved stability and safety
Authors: Gerhard Frey, Jing Wang, Kyrie Johnson, Haizhen Liu, Christina Wheeler, Charles Xing, Ana Paula Cugnetti, Patricia McNeeley, Solmarie Joyner, Cathy Chang, William J. Boyle, Jay M. Short
Journal: Cancer Research (2023)

Abstract In recent years, antibody-drug conjugates (ADCs) have become promising antitumor agents. Today, development of a new ADC faces two major challenges: on-target, off-tumor toxicity based on target expression on healthy tissue and off-target, off-tumor toxicity caused by extracellular linker vulnerability and/or premature payload release. On-target, off-tumor toxicity can be effectively eliminated by using a Conditionally Active Biologics (CAB) antibody to specifically target tumor cells. CAB technology is a proprietary platform used to engineer antibodies that target antigens in the context of diseased tissues, but not normal tissues by exploiting the unique extracellular acidic conditions found on the surface of cancer cells (Chang et al. 2021). This platform has allowed us to generate CAB antibody drug conjugates (ADCs) specific to tumor associated antigens that are often expressed on healthy tissues. CAB selectively reduces on-target toxicity, as well as off-target toxicity by eliminating target mediated drug disposition. Conventional ADCs can induce unacceptable toxicities caused by binding to antigen expressed on normal cells, resulting in the undesired release of the payload. This can severely limit the therapeutic window of the drug candidate. Two CAB-ADCs (Mecbotamab Vedotin and Ozuriftamab Vedotin) using the well-established vedotin linker with MMAE as payload are currently in phase 2 clinical trials and show promising results with increased safety profiles, with currently no signs of on-target, off-tumor toxicity. BA3361, a CAB-ADC targeting Nectin-4, showed good in vitro and in vivo efficacy data demonstrating cytotoxicity against human Nectin-4-expressing tumor cell lines and tumor regression in xenograft models using the vedotin linker (AACR 2020, Poster #4560). To eliminate vedotin linker-related off-target toxicities, we developed a NextGen Nectin-4 CAB ADC with a novel cleavable linker that is highly stable in human serum and has increased solubility. In vivo efficacy data from CDX models as well as data from non-GLP tox studies in rats and cynomolgus monkeys will be presented. In conclusion, our data indicates that the CAB-Nectin-4-ADC with its optimized linker payload, has superior serum stability while maintaining the CAB target selectivity. Reference: 1. Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches. Chang HW, Frey G, Liu H, Xing C, Steinman L, Boyle WJ, Short JM. Proc Natl Acad Sci U S A. 2021 Mar 2;118(9):e2020606118. 2. Jing Wang, Charles Xing, Haizhen Liu, Ana Paula Cugnetti, Christina Wheeler, Mathew Lucas, Gerhard Frey, Cathy Chang, William J. Boyle, Jay M. Short. Novel conditionally active ADCs (CAB ADCs): A novel class of molecules targeting solid tumors. AACR Annual Meeting 2020, Abstract #7890, Poster #4560 Citation Format: Gerhard Frey, Jing Wang, Kyrie Johnson, Haizhen Liu, Christina Wheeler, Charles Xing, Ana Paula Cugnetti, Patricia McNeeley, Solmarie Joyner, Cathy Chang, William J. Boyle, Jay M. Short. NextGen conditionally active biologic (CAB) anti-Nectin-4-ADC with improved stability and safety [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1541.